Adhesion promoting primer for coated surfaces

ABSTRACT

An expandable medical device includes a plurality of elongated struts, forming a substantially cylindrical device which is expandable from a first diameter to a second diameter. A plurality of different beneficial agents may be loaded into different openings within the struts for delivery to the tissue. For treatment of conditions such as restenosis, different agents are loaded into different openings in the device to address different biological processes involved in restenosis and are delivered at different release kinetics matched to the biological process treated. The different agents may also be used to address different diseases from the same drug delivery device. In addition, anti-thrombotic agents may be affixed to at least a portion of the surfaces of the medical device for the prevention of sub-acute thrombosis. To ensure that the different agents remain affixed to the device as well as to each other, primer layers may be utilized.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to tissue-supporting medical devices, andmore particularly to expandable, non-removable devices that areimplanted within a bodily lumen of a living animal or human to supportthe organ and maintain patency, and that have openings for delivery of aplurality of beneficial agents to the intervention site as well as asurface coating of an antithrombotic agent. The present invention alsorelates to primer coatings for use between the antithrombotic agentcoating and other therapeutic agent/polymer matrices.

2. Discussion of the Related Art

In the past, permanent or biodegradable devices have been developed forimplantation within a body passageway to maintain patency of thepassageway. These devices are typically introduced percutaneously, andtransported transluminally until positioned at a desired location. Thesedevices are then expanded either mechanically, such as by the expansionof a mandrel or balloon positioned inside the device, or expandthemselves by releasing stored energy upon actuation within the body.Once expanded within the lumen, these devices, called stents, becomeencapsulated within the body tissue and remain a permanent implant.

Known stent designs include monofilament wire coil stents (U.S. Pat. No.4,969,458); welded metal cages (U.S. Pat. Nos. 4,733,665 and 4,776,337);and, most prominently, thin-walled metal cylinders with axial slotsformed around the circumference (U.S. Pat. Nos. 4,733,665; 4,739,762;and 4,776,337). Known construction materials for use in stents includepolymers, organic fabrics and biocompatible metals, such as, stainlesssteel, gold, silver, tantalum, titanium, and shape memory alloys, suchas nickel-titanium.

U.S. Pat. No. 6,241,762, which is incorporated herein by reference inits entirety, discloses a non-prismatic stent design which remediesseveral performance deficiencies of previous stents. In addition,preferred embodiments disclosed in this patent provide a stent withlarge, non-deforming strut and link elements, which may contain holeswithout compromising the mechanical properties of the strut or linkelements, or the device as a whole. Further, these holes may serve aslarge, protected reservoirs for delivering various beneficial agents tothe device implantation site without the need for a surface coating onthe stent.

Of the many problems that may be addressed through stent-based localdelivery of beneficial agents, one of the most important is restenosis.Restenosis is a major complication that may arise following vascularinterventions such as angioplasty and the implantation of stents. Simplydefined, restenosis is a wound healing process that reduces the vessellumen diameter by extracellular matrix deposition and vascular smoothmuscle cell proliferation and which may ultimately result in renarrowingor even reocclusion of the lumen. Despite the introduction of improvedsurgical techniques, devices and pharmaceutical agents, the overallrestenosis rate for bare metal stents is still reported in the range ofabout twenty-five percent to about fifty percent within six to twelvemonths after an angioplasty procedure. To treat this condition,additional revascularization procedures are frequently required, therebyincreasing trauma and risk to the patient.

Conventional stents with surface coatings of various beneficial agentshave shown promising results in reducing restenosis. U.S. Pat. No.5,716,981, for example, discloses a stent that is surface-coated with acomposition comprising a polymer carrier and paclitaxel. The patentoffers detailed descriptions of methods for coating stent surfaces, suchas spraying and dipping, as well as the desired character of the coatingitself: it should “coat the stent smoothly and evenly” and “provide auniform, predictable, prolonged release of the anti-angiogenic factor.”Surface coatings, however, may provide little actual control over therelease kinetics of beneficial agents. These coatings are necessarilyvery thin, typically five to eight microns deep. The surface area of thestent, by comparison is very large, so that the entire volume of thebeneficial agent has a very short diffusion path to discharge into thesurrounding tissue. The resulting cumulative drug release profile ischaracterized by a large initial burst, followed by a rapid approach toan asymptote, rather than the desired “uniform, prolonged release,” orlinear release.

Increasing the thickness of the surface coating has the beneficialeffects of improving drug release kinetics including the ability tobetter control drug release and to allow increased drug loading.However, the increased coating thickness results in an increased overallthickness of the stent wall. This is undesirable for a number ofreasons, including potential increased trauma to the vessel lumen duringimplantation, reduced flow cross-section of the lumen afterimplantation, and increased vulnerability of the coating to mechanicalfailure or damage during expansion and implantation. Coating thicknessis one of several factors that affect the release kinetics of thebeneficial agent, and limitations on thickness thereby limit the rangeof release rates, durations, and the like that may be achieved.

Surface coatings may also limit the delivery of multiple drugs from astent. For example, if multiple drugs were to be released from a surfacecoating, the release rates, delivery periods and other releasecharacteristics may not be independently controlled in a facile way.However, restenosis involves multiple biological processes and may betreated most effectively by a combination of drugs selected to act onthese different biological processes.

A paper entitled “Physiological Transport Forces Govern DrugDistribution for Stent-Based Delivery” by Chao-Wei Hwang et al. hasrevealed an important interrelationship between the spatial and temporaldrug distribution properties of drug eluting stents, and cellular drugtransport mechanisms. In pursuit of enhanced mechanical performance andstructural properties, stent designs have evolved to more complexgeometries with inherent inhomogeneity in the circumferential andlongitudinal distribution of stent struts. Examples of this trend arethe typical commercially available stents which expand to a roughlydiamond or polygonal shape when deployed in a bodily lumen. Both havebeen used to deliver a beneficial agent in the form of a surfacecoating. Studies have shown that lumen tissue portions immediatelyadjacent to the struts acquire much higher concentrations of drug thanmore remote tissue portions, such as those located in the middle of the“diamond” shaped strut cells. Significantly, this concentration gradientof drug within the lumen wall remains higher over time for hydrophobicbeneficial agents, such as paclitaxel or a rapamycin, which have provento be the most effective anti-restinotics to date. Because local drugconcentrations and gradients are inextricably linked to biologicaleffects, the initial spatial distribution of the beneficial agentsources (the stent struts) is key to efficacy.

In addition to the sub-optimal spatial distribution of beneficialagents, there are further potential disadvantages with surface coatedstents. Certain fixed matrix polymer carriers frequently used in thedevice coatings typically retain a significant percent of the beneficialagent in the coating indefinitely. Since these beneficial agents may becytotoxic, for example, paclitaxel, sub-acute and chronic problems suchas chronic inflammation, late thrombosis, and late or incomplete healingof the vessel wall may occur. Additionally, the carrier polymersthemselves are often inflammatory to the tissue of the vessel wall. Onthe other hand, the use of bio-degradable polymer carriers on stentsurfaces may result in “mal-apposition” or voids between the stent andtissue of the vessel wall after the polymer carrier has degraded. Thevoids permit differential motion between the stent and adjacent tissue.Resulting problems include micro-abrasion and inflammation, stent drift,and failure to re-endothelialize the vessel wall.

Early human clinical trials suggest that there may be certaindisadvantages associated with first generation drug delivery devices.Follow-up examination of clinical trial patients at six to eighteenmonths after drug coated stent implantation indicates thatmal-apposition of stent struts to arterial walls and edge effectrestenosis may occur in significant numbers of patients. Edge effectrestenosis occurs just beyond the proximal and distal edges of the stentand progresses around the stent edges and into the interior (luminal)space, frequently requiring repeat revascularization of the patient.

Another potential disadvantage is that expansion of the stent may stressan overlying polymeric coating causing the coating to peel, crack, orrupture which may effect drug release kinetics or have other untowardeffects. These effects have been observed in first generation drugcoated stents when these stents are expanded to larger diameters,preventing their use thus far in larger diameter arteries. Further,expansion of such a coated stent in an atherosclerotic blood vessel willplace circumferential shear forces on the polymeric coating, which maycause the coating to separate from the underlying stent surface. Suchseparation may again have untoward effects including embolization ofcoating fragments causing vascular obstruction.

Another problem that may be addressed through stent-based local deliveryof beneficial agents is thrombosis. A stent may be coated with ananti-thrombotic agent in addition to one or more therapeutic agents fortreating restenosis. However, depending on the coatings on the surfaceof the stent, for example, an antithrombotic drug coating, additionallayer(s) or primer layer(s) may be preferable to enhance the adhesion ofother therapeutic agents to the coated surfaces of the stent.

SUMMARY OF THE INVENTION

The adhesion promoting primer for heparin coated surfaces of the presentinvention overcomes the difficulties briefly described above.

In accordance with one aspect, the present invention is directed to animplantable medical device. The implantable medical device comprising anintraluminal scaffold having a plurality of openings therein, a firstcoating comprising a material having a first electric charge affixed toat least a portion of a surface of the intraluminal scaffold and asurface of the plurality of openings, a second coating comprising amaterial having a second electric charge affixed to at least a portionof the first coating, the second electric charge being opposite of thefirst electric charge, and at least one therapeutic agent deposited inat least one of the plurality of openings, wherein the second coating isconfigured as an intermediate layer between the first coating and the atleast one therapeutic agent.

In accordance with another aspect, the present invention is directed toan implantable medical device. The implantable medical device comprisinga substantially cylindrical intraluminal scaffold which is expandablefrom a first diameter for delivery into a vessel, to a second diameterfor expanding the vessel, the intraluminal scaffold having a luminalsurface and an abluminal surface, the distance between the luminalsurface and the abluminal surface defining the wall thickness of theintraluminal scaffold, the intraluminal scaffold also including aplurality of openings extending from the luminal to abluminal surface, afirst coating comprising a material having a first electric chargeaffixed to at least a portion of the abluminal surface, the luminalsurface and a surface of the plurality of openings, a second coatingcomprising a material having a second electric charge affixed to atleast a portion of the first coating, the second electric charge beingopposite of the first electric charge, and at least one therapeuticagent deposited in at least one of the plurality of openings, whereinthe second coating is configured as an intermediate bonding layerbetween the first coating and the at least one therapeutic agent.

In accordance with another aspect, the present invention is directed toa method for coating an intraluminal scaffold having a plurality ofopenings therein. The method comprising applying a first coatingcomprising a material having a first electric charge to at least aportion of a surface of the intraluminal scaffold and a surface of theplurality of openings, applying a second coating comprising a materialhaving a second electric charge to at least a portion of the firstcoating, the second electric charge being opposite of the first electriccharge, and applying at least one therapeutic agent into at least one ofthe plurality of openings.

In view of the drawbacks of the prior art, it would be advantageous toprovide a stent capable of delivering a relatively large volume of abeneficial agent to a traumatized site in a vessel lumen while avoidingthe numerous potential problems associated with surface coatingscontaining beneficial agents, without increasing the effective wallthickness of the stent, and without adversely impacting the mechanicalexpansion properties of the stent.

It would further be advantageous to provide a tissue supporting devicewith different beneficial agents provided in different holes to achievea desired spatial distribution of two or more beneficial agents.

It would further be advantageous to provide a tissue supporting devicewith different beneficial agents provided in different holes to achievea desired different release kinetic for two different beneficial agentsfrom the same device.

It would further be advantageous to provide a tissue supporting devicehaving all surfaces coated with an anti-thrombotic agent and thenutilize a primer in the holes or openings therein to increase theadhesion of the one or more beneficial agents that fill the holes.

The present invention is directed to primer compositions andconfigurations for improving the adhesion of a drug delivery matrix,e.g. therapeutic agent and polymer combination, to openings of a medicaldevice, for example, a stent, that have a heparin coating. The presentinvention is particularly advantageous where the heparin coating iscovalently bonded to a metallic or polymer surface of the medicaldevice. In the present invention, the primer preferably comprises a highmolecular weight component or a low molecular weight component, and thedrug delivery matrix comprises a drug and/or other beneficial agent andan excipient, preferably a polymeric excipient. In addition, the primermay also preferably comprise a material having an opposite charge withsimilar density to that of the underlying layer, for example, heparin.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other features and advantages of the invention will beapparent from the following more particular description of preferredembodiments of the invention as illustrated in the accompanyingdrawings.

FIG. 1 is an isometric view of an expandable medical device with abeneficial agent at the ends in accordance with the present invention.

FIG. 2 is an isometric view of an expandable medical device with abeneficial agent at a central portion and no beneficial agent at theends in accordance with the present invention.

FIG. 3 is an isometric view of an expandable medical device withdifferent beneficial agents in different holes in accordance with thepresent invention.

FIG. 4 is an isometric view of an expandable medical device withdifferent beneficial agents in alternating holes in accordance with thepresent invention.

FIG. 5 is an enlarged side view of a portion of an expandable medicaldevice with beneficial agent openings in the bridging elements inaccordance with the present invention.

FIG. 6 is an enlarged side view of a portion of an expandable medicaldevice with a bifurcation opening in accordance with the presentinvention.

FIG. 7 is a cross sectional view of an expandable medical device havinga combination of a first agent, such as an anti-inflammatory agent, in afirst plurality of holes and a second agent, such as ananti-proliferative agent, in a second plurality of holes in accordancewith the present invention.

FIG. 8 is a graph of the release rates of one example of ananti-inflammatory and an anti-proliferative delivered by the expandablemedical device of FIG. 7 in accordance with the present invention.

FIGS. 9A-9C are partial diagrammatic representations of an alternateexemplary embodiment of an expandable medical device in accordance withthe present invention.

FIG. 10 illustrates a conjugation reaction between PLGA with acarboxylic acid end group and low molecular weight PEI in accordancewith the present invention.

FIG. 11 illustrates a conjugation reaction between PLGA with acarboxylic acid end group and high molecular weight or branched PEI inaccordance with the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

FIG. 1 illustrates an expandable medical device having a plurality ofholes comprising a beneficial agent for delivery to tissue by theexpandable medical device. The expandable medical device 10 illustratedin FIG. 1 is cut from a tube of material to form a cylindricalexpandable device. The expandable medical device 10 includes a pluralityof cylindrical sections 12 interconnected by a plurality of bridgingelements 14. The bridging elements 14 allow the tissue supporting deviceto bend axially when passing through the torturous path of vasculatureto a deployment site and allow the device to bend axially when necessaryto match the curvature of a lumen to be supported. Each of thecylindrical tubes 12 is formed by a network of elongated struts 18 whichare interconnected by ductile hinges 20 and circumferential struts 22.During expansion of the medical device 10 the ductile hinges 20 deformwhile the struts 18 are not deformed. Further details of one example ofthe expandable medical device are described in U.S. Pat. No. 6,241,762which is incorporated herein by reference in its entirety.

As illustrated in FIG. 1, the elongated struts 18 and circumferentialstruts 22 include openings 30, some of which comprise a beneficial agentfor delivery to the lumen in which the expandable medical device isimplanted. In addition, other portions of the device 10, such as thebridging elements 14, may include openings, as discussed below withrespect to FIG. 5. Preferably, the openings 30 are provided innon-deforming portions of the device 10, such as the struts 18, so thatthe openings are non-deforming and the beneficial agent is deliveredwithout risk of being fractured, expelled, or otherwise damaged duringexpansion of the device. A further description of one example of themanner in which the beneficial agent may be loaded within the openings30 is described in U.S. patent application Ser. No. 09/948,987, filedSep. 7, 2001, which is incorporated herein by reference in its entirety.

The exemplary embodiments of the present invention may be furtherrefined by using Finite Element Analysis and other techniques tooptimize the deployment of the beneficial agents within the openings 30.Basically, the shape and location of the openings 30, may be modified tomaximize the volume of the voids while preserving the relatively highstrength and rigidity of the struts with respect to the ductile hinges20. According to one preferred exemplary embodiment of the presentinvention, the openings have an area of at least 5×10⁻⁶ square inches,and preferably at least 7×10⁻⁶ square inches. Typically, the openingsare filled, from about fifty percent to about ninety-five percent fullof beneficial agent.

DEFINITIONS

The terms “agent,” “therapeutic agent” or “beneficial agent” as usedherein are intended to have the broadest possible interpretation and areused to include any therapeutic agent or drug, as well as inactiveagents such as barrier layers, carrier layers, therapeutic layers, orprotective layers.

The terms “drug” and “therapeutic agent” are used interchangeably torefer to any therapeutically active substance that is delivered to abodily lumen of a living being to produce a desired, usually beneficial,effect. Beneficial agents may include one or more drug or therapeuticagent.

The present invention is particularly well suited for the delivery ofantineoplastics, antiangiogenics, angiogenic factors,anti-inflammatories, immuno-suppressants such as a rapamycin,antirestenotics, antiplatelet agents, vasodilators, anti-thrombotics,antiproliferatives, such as paclitaxel, for example, and antithrombins,such as heparin, for example.

The term “erosion” means the process by which components of a medium ormatrix are bioresorbed and/or degraded and/or broken down by chemical orphysical or enzymatic processes. For example in reference tobiodegradable polymer matrices, erosion may occur by cleavage orhydrolysis of the polymer chains, thereby increasing the solubility ofthe matrix and suspended beneficial agents.

The term “erosion rate” is a measure of the amount of time it takes forthe erosion process to occur, usually reported in unit-area perunit-time.

The terms “matrix” or “bioresorbable matrix” are used interchangeably torefer to a medium or material that, upon implantation in a subject, doesnot elicit a detrimental response sufficient to result in the rejectionof the matrix. The matrix typically does not provide any therapeuticresponses itself, though the matrix may contain or surround a beneficialagent, as defined herein. A matrix is also a medium that may simplyprovide support, structural integrity or structural barriers. The matrixmay be polymeric, non-polymeric, hydrophobic, hydrophilic, lipophilic,amphiphilic, and the like. In addition, bioresorbable matrix shall alsobe understood to mean complete absorption of the matrix by the body overtime.

The term “openings” includes both through openings and recesses.

The term “pharmaceutically acceptable” refers to the characteristic ofbeing non-toxic to a host or patient and suitable for maintaining thestability of a beneficial agent and allowing the delivery of thebeneficial agent to target cells or tissue.

The term “polymer” refers to molecules formed from the chemical union oftwo or more repeating units, called monomers. Accordingly, includedwithin the term “polymer” may be, for example, dimers, trimers andoligomers. The polymer may be synthetic, naturally-occurring orsemisynthetic. In preferred form, the term “polymer” refers to moleculeswhich typically have a M_(w) greater than about 3000 and preferablygreater than about 10,000 and a M_(w) that is less than about 10million, preferably less than about a million and more preferably lessthan about 200,000. Examples of polymers include but are not limited to,poly-.alpha.-hydroxy acid esters such as, polylactic acid (PLLA orDLPLA), polyglycolic acid, polylactic-co-glycolic acid (PLGA),polylactic acid-co-caprolactone; poly (block-ethyleneoxide-block-lactide-co-glycolide) polymers (PEO-block-PLGA andPEO-block-PLGA-block-PEO); polyethylene glycol and polyethylene oxide,poly (block-ethylene oxide-block-propylene oxide-block-ethylene oxide);polyvinyl pyrrolidone; polyorthoesters; polysaccharides andpolysaccharide derivatives such as polyhyaluronic acid, poly (glucose),polyalginic acid, chitin, chitosan, chitosan derivatives, cellulose,methyl cellulose, hydroxyethylcellulose, hydroxypropylcellulose,carboxymethylcellulose, cyclodextrins and substituted cyclodextrins,such as beta-cyclodextrin sulfobutyl ethers; polypeptides and proteins,such as polylysine, polyglutamic acid, albumin; polyanhydrides;polyhydroxy alkonoates such as polyhydroxy valerate, polyhydroxybutyrate, and the like.

The term “primarily” with respect to directional delivery, refers to anamount greater than about fifty percent of the total amount oftherapeutic agent provided to a blood vessel is provided in the primarydirection.

The various exemplary embodiments of the present invention describedherein provide different beneficial agents in different openings in theexpandable device or beneficial agent in some openings and not inothers. The particular structure of the expandable medical device may bevaried without departing from the spirit of the invention. Since eachopening is filled independently, individual chemical compositions andpharmacokinetic properties may be imparted to the beneficial agent ineach opening.

One example of the use of different beneficial agents in differentopenings in an expandable medical device or beneficial agents in someopenings and not in others, is in addressing edge effect restenosis. Asdiscussed above, current generation coated stents may have a difficultywith edge effect restenosis or restenosis occurring just beyond theedges of the stent and progressing around the stent and into theinterior luminal space.

The causes of edge effect restenosis in first generation drug deliverystents are currently not well understood. It may be that the region oftissue injury due to angioplasty and/or stent implantation extendsbeyond the diffusion range of current generation beneficial agents suchas paclitaxel, which tends to partition strongly in tissue. A similarphenomenon has been observed in radiation therapies in which low dosesof radiation at the edges of stent have proven stimulatory in thepresence of an injury. In this case, radiating over a longer lengthuntil uninjured tissue is irradiated solved the problem. In the case ofdrug delivery stents, placing higher doses or higher concentrations ofbeneficial agents along the stent edges, placing different agents at thestent edges which diffuse more readily through the tissue, or placingdifferent beneficial agents or combinations of beneficial agents at theedges of the device may help to remedy the edge effect restenosisproblem.

FIG. 1 illustrates an expandable medical device 10 with “hot ends” orbeneficial agent provided in the openings 30 a at the ends of the devicein order to treat and reduce edge effect restenosis. The remainingopenings 30 b in the central portion of the device may be empty (asshown) or may contain a lower concentration of beneficial agent.

Other mechanisms of edge effect restenosis may involve the cytotoxicityof particular drugs or combinations of drugs. Such mechanisms couldinclude a physical or mechanical contraction of tissue similar to thatseen in epidermal scar tissue formation, and the stent might prevent thecontractile response within its own boundaries, but not beyond itsedges. Further, the mechanism of this latter form of restenosis may berelated to sequelae of sustained or local drug delivery to the arterialwall that is manifest even after the drug itself is no longer present inthe wall. That is, the restenosis may be a response to a form of noxiousinjury related to the drug and/or the drug carrier. In this situation,it might be beneficial to exclude certain agents from the edges of thedevice.

FIG. 2 illustrates an alternate exemplary embodiment of an expandablemedical device 200 having a plurality of openings 230 in which theopenings 230 b in a central portion of the device are filled with abeneficial agent and the openings 230 a at the edges of the deviceremain empty. The device of FIG. 2 is referred to as having “cool ends.”

In addition to use in reducing edge effect restenosis, the expandablemedical device 200 of FIG. 2 may be used in conjunction with theexpandable medical device 10 of FIG. 1 or another drug delivery stentwhen an initial stenting procedure has to be supplemented with anadditional stent. For example, in some cases the device 10 of FIG. 1with “hot ends” or a device with uniform distribution of drug may beimplanted improperly. If the physician determines that the device doesnot cover a sufficient portion of the lumen a supplemental device may beadded at one end of the existing device and slightly overlapping theexisting device. When the supplemental device is implanted, the device200 of FIG. 2 is used so that the “cool ends” of the medical device 200prevent double-dosing of the beneficial agent at the overlappingportions of the devices 10, 200.

FIG. 3 illustrates a further alternate exemplary embodiment of theinvention in which different beneficial agents are positioned indifferent holes of an expandable medical device 300. A first beneficialagent is provided in holes 330 a at the ends of the device and a secondbeneficial agent is provided in holes 330 b at a central portion of thedevice. The beneficial agent may contain different drugs, the same drugsin different concentrations, or different variations of the same drug.The exemplary embodiment of FIG. 3 may be used to provide an expandablemedical device 300 with either “hot ends” or “cool ends.”

Preferably, each end portion of the device 300 which includes the holes330 a comprising the first beneficial agent extends at least one holeand up to about fifteen holes from the edge. This distance correspondsto about 0.005 to about 0.1 inches from the edge of an unexpandeddevice. The distance from the edge of the device 300 which includes thefirst beneficial agent is preferably about one section, where a sectionis defined between the bridging elements.

Different beneficial agents comprising different drugs may be disposedin different openings in the stent. This allows the delivery of two ormore beneficial agents from a single stent in any desired deliverypattern. Alternately, different beneficial agents comprising the samedrug in different concentrations may be disposed in different openings.This allows the drug to be uniformly distributed to the tissue with anon-uniform device structure.

The two or more different beneficial agents provided in the devicesdescribed herein may comprise (1) different drugs; (2) differentconcentrations of the same drug; (3) the same drug with differentrelease kinetics, i.e., different matrix erosion rates; or (4) differentforms of the same drug. Examples of different beneficial agentscomprising the same drug with different release kinetics may usedifferent carriers to achieve the elution profiles of different shapes.Some examples of different forms of the same drug include forms of adrug having varying hydrophilicity or lipophilicity.

In one example of the device 300 of FIG. 3, the holes 330 a at the endsof the device are loaded with a first beneficial agent comprising a drugwith a high lipophilicity while holes 330 b at a central portion of thedevice are loaded with a second beneficial agent comprising the drugwith a lower lipophilicity. The first high lipophilicity beneficialagent at the “hot ends” will diffuse more readily into the surroundingtissue reducing the edge effect restenosis.

The device 300 may have an abrupt transition line at which thebeneficial agent changes from a first agent to a second agent. Forexample, all openings within 0.05 inches of the end of the device maycomprise the first agent while the remaining openings comprise thesecond agent. Alternately, the device may have a gradual transitionbetween the first agent and the second agent. For example, aconcentration of the drug in the openings may progressively increase (ordecrease) toward the ends of the device. In another example, an amountof a first drug in the openings increases while an amount of a seconddrug in the openings decreases moving toward the ends of the device.

FIG. 4 illustrates a further alternate exemplary embodiment of anexpandable medical device 400 in which different beneficial agents arepositioned in different openings 430 a, 430 b in the device in analternating or interspersed manner. In this manner, multiple beneficialagents may be delivered to tissue over the entire area or a portion ofthe area supported by the device. This exemplary embodiment will beuseful for delivery of multiple beneficial agents where combination ofthe multiple agents into a single composition for loading in the deviceis not possible due to interactions or stability problems between thebeneficial agents.

In addition to the use of different beneficial agents in differentopenings to achieve different drug concentrations at different definedareas of tissue, the loading of different beneficial agents in differentopenings may be used to provide a more even spatial distribution of thebeneficial agent delivered in instances where the expandable medicaldevice has a non-uniform distribution of openings in the expandedconfiguration.

The use of different drugs in different openings in an interspersed oralternating manner allows the delivery of two different drugs which maynot be deliverable if combined within the same polymer/drug matrixcomposition. For example, the drugs themselves may interact in anundesirable way. Alternately, the two drugs may not be compatible withthe same polymers for formation of the matrix or with the same solventsfor delivery of the polymer/drug matrix into the openings.

Further, the exemplary embodiment of FIG. 4 having different drugs indifferent openings in an interspersed arrangement provide the ability todeliver different drugs with very different desired release kineticsfrom the same medical device or stent and to optimize the releasekinetic depending on the mechanism of action and properties of theindividual agents. For example, the water solubility of an agent greatlyaffects the release of the agent from a polymer or other matrix. Ahighly water soluble compound will generally be delivered very quicklyfrom a polymer matrix, whereas, a lipophilic agent will be deliveredover a longer time period from the same matrix. Thus, if a hydrophilicagent and a lipophilic agent are to be delivered as a dual drugcombination from a medical device, it is difficult to achieve a desiredrelease profile for these two agents delivered from the same polymermatrix.

The system of FIG. 4 allows the delivery of a hydrophilic and alipophilic drug easily from the same stent. Further, the system of FIG.4 allows the delivery two agents at two different release kineticsand/or administration periods. Each of the initial release in the firsttwenty-four hours, the release rate following the first twenty-fourhours, the total administration period and any other characteristics ofthe release of the two drugs may be independently controlled. Forexample the release rate of the first beneficial agent can be arrangedto be delivered with at least forty percent (preferably at least fiftypercent) of the drug delivered in the first twenty-four hours and thesecond beneficial agent may be arranged to be delivered with less thantwenty percent (preferably less than ten percent) of the drug deliveredin the first twenty-four hours. The administration period of the firstbeneficial agent may be about three weeks or less (preferably two weeksor less) and the administration period of the second beneficial agentmay be about four weeks or more.

Restenosis or the recurrence of occlusion post-intervention, involves acombination or series of biological processes. These processes includethe activation of platelets and macrophages. Cytokines and growthfactors contribute to smooth muscle cell proliferation and upregulationof genes and metalloproteinases lead to cell growth, remodeling ofextracellular matrix, and smooth muscle cell migration. A drug therapywhich addresses a plurality of these processes by a combination of drugsmay be the most successfully antirestenotic therapy. The presentinvention provides a means to achieve such a successful combination drugtherapy.

The examples discussed below illustrate some of the combined drugsystems which benefit from the ability to release different drugs indifferent holes or openings. One example of a beneficial system fordelivering two drugs from interspersed or alternating holes is thedelivery of an anti-inflammatory agent or an immunosuppressant agent incombination with an antiproliferative agent or an anti-migratory agent.Other combinations of these agents may also be used to target multiplebiological processes involved in restenosis. The anti-inflammatory agentmitigates the initial inflammatory response of the vessel to theangioplasty and stenting and is delivered at a high rate initiallyfollowed by a slower delivery over a time period of about two weeks tomatch the peak in the development of macrophages which stimulate theinflammatory response. The antiproliferative agent is delivered at arelatively even rate over a longer time period to reduce smooth musclecell migration and proliferation.

In addition to the examples that are be given below, the following chartillustrates some of the useful two drug combination therapies which maybe achieved by placing the drugs into different openings in the medicaldevice.

PTX Epothilone Imatinibmesylate Rapamycin PKC- ApoA-I 2-Cda D Gleevecanalog Pimecrolimus 412 Dexamethasone Farglitazar Insulin VIP milano PTXx x x x x x x x 2-CdA x x x x x s Epothilone D x x x x x x Imatinib x xx x mesylate Gleevec Rapamycin x x x x x analog Pimecrolimus x x x x xPKC-412 x x x x Dexamethasone x x Farglitazar x x Insulin x VIP x ApoA-Imilano

The placement of the drugs in different openings allows the releasekinetics to be tailored to the particular agent regardless of thehydrophobilicity or lipophobicity of the drug. Examples of somearrangements for delivery of a lipophilic drug at a substantiallyconstant or linear release rate are described in WO 04/110302 publishedon Dec. 23, 2004, which is incorporated herein by reference in itsentirety. Examples of some of the arrangements for delivery ofhydrophilic drug are described in WO 04/043510, published on May 27,2004 which is incorporated herein by reference in its entirety. Thehydrophilic drugs listed above include CdA, Gleevec, VIP, insulin, andApoA-1 milano. The lipophilic drugs listed above include paclitaxel,Epothilone D, rapamycin, pimecrolimus, PKC-412 and Dexamethazone.Farglitazar is partly liphophillic and partly hydrophilic.

In addition to the delivery of multiple of drugs to address differentbiological processes involved in restenosis, the present invention maydeliver two different drugs for treatment of different diseases from thesame stent. For example, a stent may deliver an anti-proliferative, suchas paclitaxel or a limus drug from one set of openings for treatment ofrestenosis while delivering a myocardial preservative drug, such asinsulin, from other openings for the treatment of acute myocardialinfarction.

In many of the known expandable devices and for the device illustratedin FIG. 5 the coverage of the device 500 is greater at the cylindricaltube portions 512 of the device than at the bridging elements 514.Coverage is defined as the ratio of the device surface area to the areaof the lumen in which the device is deployed. When a device with varyingcoverage is used to deliver a beneficial agent contained in openings inthe device, the beneficial agent concentration delivered to the tissueadjacent the cylindrical tube portions 512 is greater that thebeneficial agent delivered to the tissue adjacent the bridging elements514. In order to address this longitudinal variation in device structureand other variations in device coverage which lead to uneven beneficialagent delivery concentrations, the concentration of the beneficial agentmay be varied in the openings at portions of the device to achieve amore even distribution of the beneficial agent throughout the tissue. Inthe case of the exemplary embodiment illustrated in FIG. 5, the openings530 a in the tube portions 512 include a beneficial agent with a lowerdrug concentration than the openings 530 b in the bridging elements 514.The uniformity of agent delivery may be achieved in a variety of mannersincluding varying the drug concentration, the opening diameter or shape,the amount of agent in the opening (i.e., the percentage of the openingfiled), the matrix material, or the form of the drug.

Another example of an application for the use of different beneficialagents in different openings is in an expandable medical device 600, asillustrated in FIG. 6, configured for use at a bifurcation in a vessel.Bifurcation devices include a side hole 610 which is positioned to allowblood flow through a side branch of a vessel. One example of abifurcation device is described in U.S. Pat. No. 6,293,967 which isincorporated herein by reference in its entirety. The bifurcation device600 includes the side hole feature 610 interrupting the regular patternof beams which form a remainder of the device. Since an area around abifurcation is a particularly problematic area for restenosis, aconcentration of an antiproliferative drug may be increased in openings830 a at an area surrounding the side hole 610 of the device 600 todeliver increased concentrations of the drug where needed. The remainingopenings 630 b in an area away from the side opening contain abeneficial agent with a lower concentration of the antiproliferative.The increased antiproliferative delivered to the region surrounding thebifurcation hole may be provided by a different beneficial agentcontaining a different drug or a different beneficial agent containing ahigher concentration of the same drug.

In addition to the delivery of different beneficial agents to the muralor abluminal side of the expandable medical device for treatment of thevessel wall, beneficial agents may be delivered to the luminal side ofthe expandable medical device to prevent or reduce thrombosis. Drugswhich are delivered into the blood stream from the luminal side of thedevice may be located at a proximal end of the device or a distal end ofthe device.

The methods for loading different beneficial agents into differentopenings in an expandable medical device may include known techniquessuch as dipping and coating and also known piezoelectric micro-jettingtechniques. Micro-injection devices may be computer controlled todeliver precise amounts of two or more liquid beneficial agents toprecise locations on the expandable medical device in a known manner.For example, a dual agent jetting device may deliver two agentssimultaneously or sequentially into the openings. When the beneficialagents are loaded into through openings in the expandable medicaldevice, a luminal side of the through openings may be blocked duringloading by a resilient mandrel allowing the beneficial agents to bedelivered in liquid form, such as with a solvent. The beneficial agentsmay also be loaded by manual injection devices.

EXAMPLE 1

FIG. 7 illustrates a dual drug stent 700 having an anti-inflammatoryagent and an antiproliferative agent delivered from different holes inthe stent to provide independent release kinetics of the two drugs whichare specifically programmed to match the biological processes ofrestenosis. According to this example, the dual drug stent includes ananti-inflammatory agent pimecrolimus in a first set of openings 710 incombination with the antiproliferative agent paclitaxel in a second setof openings 720. Each agent is provided in a matrix material within theholes of the stent in a specific inlay arrangement designed to achievethe release kinetics illustrated in FIG. 8. Each of the drugs aredelivered primarily murally for treatment of restenosis.

As illustrated in FIG. 7, pimecrolimus is provided in the stent fordirectional delivery to the mural side of the stent by the use of abarrier 712 at the luminal side of the hole. The barrier 712 is formedby a biodegradable polymer. The pimecrolimus is loaded within the holesin a manner which creates a release kinetics having dual phases. A firstphase of the release of pimecrolimus is provided by a murally locatedregion 716 of the matrix which has a fast release formulation includingpimecrolimus and biodegradable polymer (PLGA) with a high percentage ofdrug, such as about ninety percent drug to about ten percent polymer. Asecond phase of the release is provided by a central region 714 of thematrix with pimecrolimus and biodegradable polymer (PLGA) in a ratio ofabout fifty percent drug to fifty percent polymer. As may be seen on thegraph of FIG. 8, the first phase of the pimecrolimus release deliversabout fifty percent of the loaded drug in about the first twenty-fourhours. The second phase of the release delivers the remaining fiftypercent over about two weeks. This release is specifically programmed tomatch the progression of the inflammatory process following angioplastyand stenting. In addition to or as an alternative to changing the drugconcentration between the two regions to achieve the two phase release,different polymers or different comonomer ratios of the same polymer maybe used in two drug different regions to achieve the two differentrelease rates.

The paclitaxel is loaded within the openings 720 in a manner whichcreates a release kinetic having a substantially linear release afterthe first approximately twenty-four hours, as illustrated in FIG. 8. Thepaclitaxel openings 720 are loaded with three regions including a baseregion 722 of primarily polymer with minimal drug at a luminal side ofthe hole, a central region 724 with paclitaxel and polymer (PLGA)provided in a concentration gradient, and a cap region 726 withprimarily polymer which controls release of the paclitaxel. Thepaclitaxel is released with an initial release in the first day of aboutfive to about fifteen percent of the total drug load followed by asubstantially linear release for about twenty to ninety days. Additionalexamples of arrangements for paclitaxel in the holes with aconcentration gradient are described in WO 04/110302 set forth above.

FIG. 7 illustrates the drug, barrier, and cap regions as distinctregions within the openings for ease of illustration. It should beunderstood that these regions indistinct and formed by a blending of thedifferent areas. Thus, although the barrier layers are primarily polymerwithout drug, depending on the manufacturing processes employed, somesmall amount of drug of the subsequent region can be incorporation intothe barrier region.

The amount of the drugs delivered varies depending on the size of thestent. For a three mm by six mm stent the amount of pimecrolimus isabout fifty to about three hundred micrograms preferably about onehundred to about two hundred fifty micrograms. The amount of paclitaxeldelivered from this stent is about five to about fifty microgramspreferably about ten to about thirty micrograms. In one example, abouttwo hundred micrograms of pimecrolimus and about twenty micrograms ofpaclitaxel are delivered. The drugs may be located in alternating holesin the stent. However, in view of the large difference in the doses tobe delivered between the two drugs, it may be desirable to place thepaclitaxel in every third of fourth hole in the stent. Alternatively,the holes for delivery of the low dose drug (paclitaxel) may be madesmaller than the holes for the high dose.

The polymer/drug inlays are formed by computer controlled piezoelectricinjection techniques as described in WO 04/026182 published on Apr. 1,2004, which is incorporated herein by reference in its entirety. Theinlays of the first agent may be formed first followed by the inlays ofthe second agent using the piezoelectric injector. Alternately, thesystem of WO 04/02182 may be equipped with dual piezoelectric dispensersfor dispensing the two agents at the same time.

EXAMPLE 2

According to this example, the dual drug stent includes the Gleevec inthe first set of openings 710 in combination with the antiproliferativeagent paclitaxel in the second set of openings 720. Each agent isprovided in a matrix material within the holes of the stent in aspecific inlay arrangement designed to achieve the release kineticsillustrated in FIG. 8.

The Gleevec is delivered with a two phase release including a highinitial release in the first day and then a slow release for one to twoweeks. The first phase of the Gleevec release delivers about fiftypercent of the loaded drug in about the first twenty-four hours. Thesecond phase of the release delivers the remaining fifty percent overabout one-two weeks. The paclitaxel is loaded within the openings 720 ina manner which creates a release kinetics having a substantially linearrelease after the first approximately twenty-four hours, as illustratedin FIG. 8 and as described above in Example 1.

The amount of the drugs delivered varies depending on the size of thestent. For a three mm by six mm stent the amount of Gleevec is about twohundred to about five hundred micrograms, preferably about three hundredto about four hundred micrograms. The amount of paclitaxel deliveredfrom this stent is about five to about fifty micrograms, preferablyabout ten to about thirty micrograms. As in Example 1, the drugs may belocated in alternating holes in the stent or interspersed in anon-alternating manner. The polymer/drug inlays are formed in the mannerdescribed in Example 1.

EXAMPLE 3

According to this example, the dual drug stent includes the PKC-412 (acell growth regulator) in the first set of openings in combination withthe antiproliferative agent paclitaxel in the second set of openings.Each agent is provided in a matrix material within the holes of thestent in a specific inlay arrangement designed to achieve the releasekinetics discussed below.

The PKC-412 is delivered at a substantially constant release rate afterthe first approximately twenty-four hours, with the release over aperiod of about four to sixteen weeks, preferably about six to twelveweeks. The paclitaxel is loaded within the openings in a manner whichcreates a release kinetic having a substantially linear release afterthe first approximately twenty-four hours, with the release over aperiod of about four to sixteen weeks, preferably about six to twelveweeks.

The amount of the drugs delivered varies depending on the size of thestent. For a three mm by six mm stent the amount of PKC-412 is about onehundred to about four hundred micrograms, preferably about one hundredfifty to about two hundred fifty micrograms. The amount of paclitaxeldelivered from this stent is about five to about fifty micrograms,preferably about ten to about thirty micrograms. As in Example 1, thedrugs may be located in alternating holes in the stent or interspersedin a non-alternating manner. The polymer/drug inlays are formed in themanner described in Example 1.

Therapeutic Agents

The present invention relates to the delivery of anti-restenotic agentsincluding paclitaxel, rapamycin, cladribine (CdA), and theirderivatives, as well as other cytotoxic or cytostatic agents andmicrotubule stabilizing agents. Although anti-restenotic agents havebeen primarily described herein, the present invention may also be usedto deliver other agents alone or in combination with anti-restenoticagents. Some of the therapeutic agents for use with the presentinvention which may be transmitted primarily luminally, primarilymurally, or both and may be delivered alone or in combination include,but are not limited to, antiproliferatives, antithrombins,immunosuppressants including sirolimus, antilipid agents,anti-inflammatory agents, antineoplastics, antiplatelets, angiogenicagents, anti-angiogenic agents, vitamins, antimitotics,metalloproteinase inhibitors, NO donors, estradiols, anti-sclerosingagents, and vasoactive agents, endothelial growth factors, estrogen,beta blockers, AZ blockers, hormones, statins, insulin growth factors,antioxidants, membrane stabilizing agents, calcium antagonists,retenoid, bivalirudin, phenoxodiol, etoposide, ticlopidine,dipyridamole, and trapidil alone or in combinations with any therapeuticagent mentioned herein. Therapeutic agents also include peptides,lipoproteins, polypeptides, polynucleotides encoding polypeptides,lipids, protein-drugs, protein conjugate drugs, enzymes,oligonucleotides and their derivatives, ribozymes, other geneticmaterial, cells, antisense, oligonucleotides, monoclonal antibodies,platelets, prions, viruses, bacteria, and eukaryotic cells such asendothelial cells, stem cells, ACE inhibitors, monocyte/macrophages orvascular smooth muscle cells to name but a few examples. The therapeuticagent may also be a pro-drug, which metabolizes into the desired drugwhen administered to a host. In addition, therapeutic agents may bepre-formulated as microcapsules, microspheres, microbubbles, liposomes,niosomes, emulsions, dispersions or the like before they areincorporated into the therapeutic layer. Therapeutic agents may also beradioactive isotopes or agents activated by some other form of energysuch as light or ultrasonic energy, or by other circulating moleculesthat can be systemically administered. Therapeutic agents may performmultiple functions including modulating angiogenesis, restenosis, cellproliferation, thrombosis, platelet aggregation, clotting, andvasodilation.

Anti-inflammatories include but are not limited to non-steroidalanti-inflammatories (NSAID), such as aryl acetic acid derivatives, e.g.,Diclofenac; aryl propionic acid derivatives, e.g., Naproxen; andsalicylic acid derivatives, e.g., Diflunisal. Anti-inflammatories alsoinclude glucocoriticoids (steroids) such as dexamethasone, aspirin,prednisolone, and triamcinolone, pirfenidone, meclofenamic acid,tranilast, and nonsteroidal anti-inflammatories. Anti-inflammatories maybe used in combination with antiproliferatives to mitigate the reactionof the tissue to the antiproliferative.

The agents may also include anti-lymphocytes; anti-macrophagesubstances; immunomodulatory agents; cyclooxygenase inhibitors;anti-oxidants; cholesterol-lowering drugs; statins and angiotens inconverting enzyme (ACE); fibrinolytics; inhibitors of the intrinsiccoagulation cascade; antihyperlipoproteinemics; and anti-plateletagents; anti-metabolites, such as 2-chlorodeoxy adenosine (2-CdA orcladribine); immuno-suppressants including sirolimus, everolimus,tacrolimus, etoposide, and mitoxantrone; anti-leukocytes such as 2-CdA,IL-1 inhibitors, anti-CD116/CD18 monoclonal antibodies, monoclonalantibodies to VCAM or ICAM, zinc protoporphyrin; anti-macrophagesubstances such as drugs that elevate NO; cell sensitizers to insulinincluding glitazones; high density lipoproteins (HDL) and derivatives;and synthetic facsimile of HDL, such as lipator, lovestatin,pranastatin, atorvastatin, simvastatin, and statin derivatives;vasodilators, such as adenosine, and dipyridamole; nitric oxide donors;prostaglandins and their derivatives; anti-TNF compounds; hypertensiondrugs including Beta blockers, ACE inhibitors, and calcium channelblockers; vasoactive substances including vasoactive intestinalpolypeptides (VIP); insulin; cell sensitizers to insulin includingglitazones, P par agonists, and metformin; protein kinases; antisenseoligonucleotides including resten-NG; antiplatelet agents includingtirofiban, eptifibatide, and abciximab; cardio protectants including,VIP, pituitary adenylate cyclase-activating peptide (PACAP), apoA-Imilano, amlodipine, nicorandil, cilostaxone, and thienopyridine;cyclooxygenase inhibitors including COX-1 and COX-2 inhibitors; andpetidose inhibitors which increase glycolitic metabolism includingomnipatrilat. Other drugs which may be used to treat inflammationinclude lipid lowering agents, estrogen and progestin, endothelinreceptor agonists and interleukin-6 antagonists, and Adiponectin.Therapeutic agents may also include phosphodiesterase inhibitors (PDEi),such as cilastazol and adenosine receptor agonists, preferably A_(2A)receptor, agonists such as regadenoson.

Agents may also be delivered using a gene therapy-based approach incombination with an expandable medical device. Gene therapy refers tothe delivery of exogenous genes to a cell or tissue, thereby causingtarget cells to express the exogenous gene product. Genes are typicallydelivered by either mechanical or vector-mediated methods.

Some of the agents described herein may be combined with additives whichpreserve their activity. For example additives including surfactants,antacids, antioxidants, and detergents may be used to minimizedenaturation and aggregation of a protein drug. Anionic, cationic, ornonionic surfactants may be used. Examples of nonionic excipientsinclude but are not limited to sugars including sorbitol, sucrose,trehalose; dextrans including dextran, carboxy methyl (CM) dextran,diethylamino ethyl (DEAE) dextran; sugar derivatives includingD-glucosaminic acid, and D-glucose diethyl mercaptal; syntheticpolyethers including polyethylene glycol (PEO) and polyvinyl pyrrolidone(PVP); carboxylic acids including D-lactic acid, glycolic acid, andpropionic acid; surfactants with affinity for hydrophobic interfacesincluding n-dodecyl-.beta.-D-maltoside, n-octyl-.beta.-D-glucoside,PEO-fatty acid esters (e.g. stearate (myrj 59) or oleate),PEO-sorbitan-fatty acid esters (e.g. Tween 80, PEO-20 sorbitanmonooleate), sorbitan-fatty acid esters (e.g. SPAN 60, sorbitanmonostearate), PEO-glyceryl-fatty acid esters; glyceryl fatty acidesters (e.g. glyceryl monostearate), PEO-hydrocarbon-ethers (e.g. PEO-10oleyl ether; triton X-100; and Lubrol. Examples of ionic detergentsinclude but are not limited to fatty acid salts including calciumstearate, magnesium stearate, and zinc stearate; phospholipids includinglecithin and phosphatidyl choline; (PC) CM-PEG; cholic acid; sodiumdodecyl sulfate (SDS); docusate (AOT); and taumocholic acid.

In accordance with another exemplary embodiment, a stent or intraluminalscaffold as described herein, may be coated with an anti-thromboticagent in addition to one or more therapeutic agents deposited in theholes or openings. In one exemplary embodiment, the stent may befabricated with the openings therein and prior to the addition ordeposition of other therapeutic agents into the openings, ananti-thrombotic agent, with or without a carrier vehicle (polymer orpolymeric matrix) may be affixed to the stent or a portion thereof. Inthis exemplary embodiment, the luminal and abluminal surfaces of thestent may be coated with the anti-thrombotic agent or coating, as wellas the surfaces of the walls of the openings. In an alternativeexemplary embodiment, a stent may first be coated with ananti-thrombotic agent or coating and then the openings may befabricated. In this exemplary embodiment, only the luminal and abluminalsurfaces would have the anti-thrombotic agent or coating and not thewalls of the openings. In each of these embodiments any number ofanti-thrombotic agents may be affixed to all or portions of the stents.In addition, any number of known techniques may be utilized to affix theanti-thrombotic agent to the stent such as that utilized with theHEPACOAT™ on the Bx Velocity® Coronary Stent from Cordis Corporation.Alternatively, the stents may be manufactured with a rough surfacetexture or have a micro-texture to enhance cell attachment andendothelialization, independently of or in addition to theanti-thrombotic coating. In addition, any number of therapeutic agentsmay be deposited into the openings and different agents may be utilizedin different regions of the stent.

As described above, it is important to note that any number of drugs andor agents may be utilized in accordance with the present inventionincluding: antiproliferative/antimitotic agents including naturalproducts such as vinca alkaloids (i.e. vinblastine, vincristine, andvinorelbine), paclitaxel, epidipodophyllotoxins (i.e. etoposide,teniposide), antibiotics (dactinomycin (actinomycin D) daunorubicin,doxorubicin and idarubicin), anthracyclines, mitoxantrone, bleomycins,plicamycin (mithramycin) and mitomycin, enzymes (L-asparaginase whichsystemically metabolizes L-asparagine and deprives cells which do nothave the capacity to synthesize their own asparagine); antiplateletagents such as G(GP)II_(b)III_(a) inhibitors and vitronectin receptorantagonists; antiproliferative/antimitotic alkylating agents such asnitrogen mustards (mechlorethamine, cyclophosphamide and analogs,melphalan, chlorambucil), ethylenimines and methylmelamines(hexamethylmelamine and thiotepa), alkyl sulfonates-busulfan,nirtosoureas (carmustine (BCNU) and analogs, streptozocin),trazenes—dacarbazinine (DTIC); antiproliferative/antimitoticantimetabolites such as folic acid analogs (methotrexate), pyrimidineanalogs (fluorouracil, floxuridine, and cytarabine), purine analogs andrelated inhibitors (mercaptopurine, thioguanine, pentostatin and2-chlorodeoxyadenosine {cladribine}); platinum coordination complexes(cisplatin, carboplatin), procarbazine, hydroxyurea, mitotane,aminoglutethimide; hormones (i.e. estrogen); anticoagulants (heparin,synthetic heparin salts and other inhibitors of thrombin); fibrinolyticagents (such as tissue plasminogen activator, streptokinase andurokinase), aspirin, dipyridamole, ticlopidine, clopidogrel, abciximab;antimigratory; antisecretory (breveldin); antiinflammatory: such asadrenocortical steroids (cortisol, cortisone, fludrocortisone,prednisone, prednisolone, 6α-methylprednisolone, triamcinolone,betamethasone, and dexamethasone), non-steroidal agents (salicylic acidderivatives i.e. aspirin; para-aminophenol derivatives i.e.acetominophen; indole and indene acetic acids (indomethacin, sulindac,and etodalac), heteroaryl acetic acids (tolmetin, diclofenac, andketorolac), arylpropionic acids (ibuprofen and derivatives), anthranilicacids (mefenamic acid, and meclofenamic acid), enolic acids (piroxicam,tenoxicam, phenylbutazone, and oxyphenthatrazone), nabumetone, goldcompounds (auranofin, aurothioglucose, gold sodium thiomalate);immunosuppressives: (cyclosporine, tacrolimus (FK-506), sirolimus(rapamycin), azathioprine, mycophenolate mofetil); angiogenic agents:vascular endothelial growth factor (VEGF), fibroblast growth factor(FGF) platelet derived growth factor (PDGF), erythropoetin; angiotensinreceptor blocker; nitric oxide donors; anti-sense oligionucleotides andcombinations thereof; cell cycle inhibitors, mTOR inhibitors, and growthfactor signal transduction kinase inhibitors.

Referring now to FIGS. 9A, 9B and 9C, there is illustrated adiagrammatic representation of a portion of a stent.

As illustrated in FIG. 9A the stent 900 comprises a plurality ofsubstantially circular openings 902. In this exemplary embodiment, theplurality of substantially circular openings 902 extend through the wallof the stent 900. In other words, the plurality of substantiallycircular openings 902 extend from the abluminal surface of the stent 904to the abluminal surface of the stent 906, wherein the wall thickness isdefined as the distance between the luminal and abluminal surfaces. Inother embodiments; however, the openings need not extend through thewall of the stent 900. For example, the openings or reservoirs mayextend partially from either the luminal or abluminal surfaces or both.The stent 900 in FIG. 9A has untreated surfaces 904 and 906 and emptyopenings 902.

In FIG. 9B, at least one surface has been coated with a therapeuticagent 908. The therapeutic agent preferably comprises an anti-thromboticagent such as heparin; however, any anti-thrombotic agent may beutilized. The anti-thrombotic agent may be affixed utilizing anytechnique as briefly described above. In this exemplary embodiment, boththe abluminal and luminal surfaces have an anti-thrombotic agent affixedthereto. In addition, as there is nothing in the plurality ofsubstantially circular openings 902 at this juncture, the walls of theopenings 902 may also have some anti-thrombotic agent affixed thereto.The amount of anti-thrombotic agent affixed to the walls of the openings910 depends on how the agent is affixed. For example, if the agent isaffixed by dip coating, the walls of the openings will have more agentaffixed thereto than if the agent is affixed utilizing a spray coatingtechnique. As described herein, in this exemplary embodiment, allexposed surfaces have a substantial anti-thrombotic coating affixedthereto; however, in alternate exemplary embodiments, only specificsurfaces may have an anti-thrombotic affixed thereto. For example, inone exemplary embodiment, only the surface in contact with the blood maybe treated with the anti-thromobotic agent. In yet another alternateexemplary embodiment, one or both surfaces may be coated with theanti-thrombotic agent while the walls of the openings are not. This maybe accomplished in a number of ways including plugging the openingsprior to coating or creating the openings after the anti-thromboticagent is affixed.

FIG. 9C illustrates a completed stent in accordance with this exemplaryembodiment. As illustrated in this figure, the plurality ofsubstantially circular openings 902 have been filled with one or moretherapeutic agents for treating vascular diseases such as restenosis andinflammation or any other dieses as described herein. Each opening 902may be filled with the same therapeutic agent or different agents asdescribed in detail above. As illustrated in the figure, these differentagents 912, 914 and 916 are used in a particular pattern; however, asdetailed above, any combination is possible as well as utilizing a singeagent with different concentrations. The drugs, such as a rapamycin, maybe deposited in the openings 902 in any suitable manner. Techniques fordepositing the agent include micro-pippetting and/or ink-jet fillingmethods. In one exemplary embodiment, the drug filling may be done sothat the drug and/or drug/polymer matrix in the opening will be belowthe level of the stent surfaces so that there is no contact with thesurrounding tissue. Alternately, the openings may be filled so that thedrug and/or drug/polymer matrix may contact the surrounding tissue. Inaddition, the total dose of each of the drugs, if multiple drugs areutilized, may be designed with maximal flexibility. Additionally, therelease rate of each of the drugs may be controlled individually. Forexample, the openings near the ends may contain more drugs to treat edgerestenosis.

In accordance with this exemplary embodiment, the hole or openings maybe configured not only for the most efficacious drug therapy, but alsofor creating a physical separation between different drugs. Thisphysical separation may aid in preventing the agents from interacting.

As used herein, rapamycin includes rapamycin and all analogs,derivatives and conjugates that bind to FKBP12, and other immunophilinsand possesses the same pharmacologic properties as rapamycin includinginhibition of TOR. In addition, all drugs and agents described herein intheir analogs, derivatives and conjugates.

As described herein, a stent having through-holes, holes, reservoirs oropenings therein may be coated with an anti-thrombotic agent and/or drugor combination of drugs such as those described herein, and the openingsfilled with one or more therapeutic agents alone or in combination withone or more polymers. Essentially, the stent may be fabricated with theopenings therein and prior to the addition or deposition of therapeuticagents alone or in combination with one or more polymers into theopenings, an anti-thrombotic agent, with or without a carrier vehicle,may be affixed to the stent or a portion thereof. In the exemplaryembodiment as described herein, the luminal and abluminal surfaces ofthe stent as well as the surfaces of the walls of the openings may becoated with the anti-thromobotic agent. In this exemplary embodiment,the anti-thrombotic agent comprises heparin or its various derivativessuch as low molecular-weight heparin (LMWH), although any number ofsuitable anti-thrombotic agents may be utilized. Heparin and/or LMWHhave very high negative charges.

The entire surface of the stent described herein, including the interiorsurfaces of the through-holes or openings that become reservoirs for thetherapeutic agent and/or combination polymers and therapeutic agent, isfirst given a covalently bonded heparin coating. The heparin coatingitself is bonded to the metal surface of the stent by its own primercomprising alternating layers of poly(ethyleneimine), a stronglycationic polymer known by the abbreviation PEI, and dextran sulfate, apolymeric anion. The application of this type of primer is known in theart and is set forth in a number of patents, including U.S. Pat. Nos.5,213,898, 5,049,403, 6,461,665 and 6,767,405. More specifically, theheparin is covalently bonded to the primer, including the PEI-dextransulfate layers, which is in turn bonded to the metal surface. Once allsurfaces are coated with the heparin mixture, each of the holes orreservoirs are filled utilizing one of the processes described herein.

In accordance with another exemplary embodiment, the present inventionis directed to primer compositions and configurations for improving theadhesion of a drug delivery matrix, e.g. therapeutic agent and polymercombination, to a heparin coated surface of a medical device, forexample, a stent. The present invention is particularly advantageouswhere the heparin coating is covalently bonded to a metallic or polymersurface of the medical device. In the present invention, the primerpreferably comprises a high molecular weight component or a lowmolecular weight component, and the drug delivery matrix comprises adrug and/or other beneficial agent and an excipient, preferably apolymeric excipient. In addition, the primer may also preferablycomprise a material having an opposite electrical charge and similarcharge density to that of the underlying layer, for example, heparin.

The concept of a primer on top of a heparin layer or coating to increasethe bonding of a heparin coated surface to any other matrix or coatingis unique given that typically the heparin surface is utilized to conferanti-thromobotic properties and hence will not be covered in practicaluses. In the present invention, it is only the interior wall surfaces ofthe holes or openings in the stent that hold the drug-polymer reservoirsthat will be covered with the primer of the present invention, thusincreasing the adhesion between the two layers and limiting thepotential loss of the drug-polymer matrix without substantiallyaffecting the heparin surface outside the reservoirs. It is important tonote that the heparin blocking primers in accordance with the presentinvention are biocompatible in their original intended uses.

The primer of the present invention may be utilized with any type ofstent. In the exemplary embodiment described herein, the primer isutilized with the stent or stents illustrated in FIGS. 1, 2, 3 and 4.

In accordance with one exemplary embodiment, the primer comprisespolymer-poly(ethyleneimine) conjugates, for examplepolylactic-co-glycolic acid (PLGA) and poly(ethyleneimine) PEI and/orPLGA-protamine. Poly(ethyleneimine) is a strongly cationic polymer thatbinds to certain negatively charged proteins or polysaccharides. Inaddition to PEI, the other material useful in this conjugate isprotamine. Protamine is an approved low molecular weight protein drugthat is utilized as an antidote to heparin. It is sparsely solution inwater. In this manner, the primer may simultaneously interact stronglywith both the heparin coating and the drug containing matrix, thusimproving the adhesion between the two substances. Since heparin is apoly(anionic) species, it is anticipated that a poly(cationic) speciessuch as protamine would bond well to the heparin, but would besufficiently hydrophobic in the other sections of its structure to allowgood bonding of the PLGA component of the drug polymer matrix in thereservoir.

The bonding reactions between PLGA and PEI and PEI and heparin may beionic-bonding or covalent-bonding reactions. FIG. 10 illustrates anexample of covalent-bonding between PLGA and PEI. More specifically,FIG. 10 illustrates the conjugation reaction between PLGA with acarboxylic acid end group and low molecular weight PEI. Alternatively,the primer may comprise a high molecular weight PEI or a branched PEI.Referring to FIG. 11, there is illustrated the conjugation reactionbetween PLGA with a carboxylic acid end group and a high molecularweight or branched PEI. As illustrated, the reaction may be configuredfor a one-to-one ratio or a conjugate of PLGA-PEI-PLGA for a 2:1 ratiobetween PLGA and PEI.

The Table below illustrates the effectiveness of PEI as a primer forincreasing the adhesion of the drug/polymer complex to the heparincoated surfaces. The test stents are immersed in a testing mediumcomprising a phosphate buffer saline and bovine serum albumin whichsimulates physiological fluid conditions. The drug/polymer complexcomprises a rapamycin and PLGA.

Percent (%) of Empty Reservoirs versus Initial Total Reservoirs Heparin(after immersion in PBS-BSA) coated Day Day Day Day Day Day Day Day DayDay Day Day stent Initial 7 14 21 28 30 35 42 49 60 75 90 No primer Avg  0% — 0% 0.3%   3.1%   — 3.7%   4.1%   4.8%   4.8%   5.1%   5.3%  Stdev   0% — 0% 0.4%   2.1%   — 2.0%   2.0%   1.2%   1.2%   1.3%  1.5%   RSD n/a — n/a 124.9%    68.3%   — 56.0%   48.5%   25.3%   25.3%  25.1%   28.4%   Primed with Avg 0.0% 0.0% — — — 0.0%   0.0%   0.25% PEIStdev 0.0% 0.0% — — — 0.0%   0.0%   (linear) in RSD n/a n/a — — — n/an/a Water Primed with Avg   0% — 0% 0% 0% — 0.1%   0.1%   0.1%   0.1%  0.1%   0.1%   0.5% PEI Stdev   0% — 0% 0% 0% — 0% 0% 0% 0% 0% 0%(linear) in RSD n/a — n/a n/a n/a — n/a n/a n/a n/a n/a n/a Water Primedwith Avg   0% — 0% 0% 0% — 0.1%   0.1%   0.1%   0.1%   0.1%   0.1%  0.5% PEI Stdev   0% — 0% 0% 0% — 0% 0% 0% 0% 0% 0% (linear) in RSD n/a —n/a n/a n/a — n/a n/a n/a n/a n/a n/a DMSO Primed with Avg   0% — 0% 0%0% — 0% 0% 0% 0% 0% 0% 0.5% PEI Stdev   0% — 0% 0% 0% — 0% 0% 0% 0% 0%0% (branched) RSD n/a — n/a n/a n/a — n/a n/a n/a n/a n/a n/a in WaterPrimed with Avg   0% — 0% 0% 0% — 0% 0% 0% 0% 0% 0% 0.5% PEI Stdev   0%— 0% 0% 0% — 0% 0% 0% 0% 0% 0% (branched) RSD n/a — n/a n/a n/a — n/an/a n/a n/a n/a n/a in DMSO Primed with Avg 0.0% 0.0% — — — 0.0%  0.0%   0.75% PEI Stdev 0.0% 0.0% — — — 0.0%   0.0%   (linear) in RSD n/an/a — — — n/a n/a Water

In an alternate exemplary embodiment, the primer may comprise lowmolecular weight complexing cations to heparin, including benzalkoniumchloride and/or oligomeric arginine peptides, or high molecular weightcomplexing cations, including polylysine, poly(arginine), protamine,poly(dimethylaminoethyl) methacrylate or poly (dimethylaminoethyl)acrylate.

In accordance with the present invention, the process for increasingadhesion of the drug complex to the heparin may include the applicationof the adhesion promoting primer followed by polymer/drug fill solutionor the application of the adhesion promoting primer followed bycarboxyl-ended PLGA or a blend of carboxyl-ended and regular PLGA andPLGA/drug fill solution.

The primer of the present invention will be applied to the interior,heparin coated walls of the holes or openings in the stent prior to theopenings being filled with a local drug delivery matrix. In other words,in the finished drug eluting stent, the primer will occupy a spacebetween the surface of the heparin coating and the body of the drugdelivery matrix and will increase the adhesion between the heparincoating and the drug delivery matrix. The enhancement of adhesion isachieved through multiple factors, including the reduction ofosmolarity/water infiltration of the heparin coating in use after thecharge neutralization by a cationic primer, reduced aqueous solubilityof heparin/cationic primer complex as compared to the heparin surfacealone, ionic bonding, covalent bonding and better physical adhesionbetween the primer and the polymer/drug matrix due to surface tensionand the like.

In another exemplary embodiment of the present invention, the primer ofthe present invention will preferably have a portion of its molecularstructure that is positively charged for bonding to the negativelycharged heparin coating, and a portion that is hydrophobic, hydrophilic,or balanced for bonding to the polymer component of the drug deliverymatrix. This portion of the primer will vary depending on the nature ofthe drug delivery matrix. More specifically, the primer is designed toimprove the adhesion of the drug delivery matrix to the heparin coatedopenings of the stent so that none or substantially none of the openingsor reservoirs lose their contents when the stent comes into contact withwater based fluids, such as saline, blood and/or intercellular fluid.

Although the primer of the present invention has been describedspecifically to increasing the adhesion between the heparin coatedinterior walls of a stent reservoir and the drug/polymer mixture fillingthe reservoir, it may be useful for the attachment or bonding of anysubstrate to a portion of a heparin coated surface. For example, bloodcontacting plastic medical devices are often coated with heparin tominimize thrombosis on the device, but it may be desired to bond laterto that surface. A mixture of the primers of the present invention in asolvent could be applied to a selected area of the device, the solventevaporated to provide a primer coated area on the heparin surface, thensubsequently a new subsystem could be bonded to the primer covered area.

The primer material will be advantageously applied as a solution of thepolymeric primer in a solvent such as dimethyl sulfoxide (DMSO),N-methylpyrrolidone, or water mixtures thereof and may be introducedinto the reservoirs using any of the filling techniques described in theinstant application. Such a primer solution could then be dried toprovide the coating of the primer layer over the heparin coated surface.Preferably, the application of the primer layer will require only asingle deposition step in the stent filling process. The selection of asuitable solvent for the deposition of a cationic primer is determinedprimarily by its ability to dissolve a primer and its compatibility withthe filling apparatus and process described herein.

The present invention may be simply characterized as an implantablemedical device. The medical device comprises an intraluminal scaffoldhaving a plurality of openings therein, a first coating comprising amaterial having a first electric charge affixed to at least a portion ofa surface of the intraluminal scaffold and a surface of the plurality ofopenings, a second coating comprising a material having a secondelectric charge affixed to at least a portion of the first coating, thesecond electric charge being opposite of the first electric charge, andat least one therapeutic agent deposited in at least one of theplurality of openings, wherein the second coating is configured as anintermediate layer between the first coating and the at least onetherapeutic agent.

The first coating may comprise any suitable anti-thrombotic as describedherein. For example, a polysaccharide such as heparin may be utilized.The second coating may comprise a polymeric cation or a polymericconjugate having cationic segments as described herein. Examples ofpolymeric cations include oligomeric arginine peptides, polylysine,poly(arginine), protamine, poly(dimethylaminoethyl) poly(ethyleneimine).Examples of polymeric cationic conjugates include a first component suchas polylactic-co-glycolic acid and the second component comprises any ofthe cations set forth above. The therapeutic agent may comprise ananti-restenotic, an anti-inflammatory, an anti-thrombotic, ananti-proliferative, an agent for minimizing damage to infarcted tissueor any combination thereof.

In a more general sense, the concept of the present invention may beexpanded to include primers that increase the bonding strength betweenhydrophilic and hydrophobic surfaces. For example, other hydrophilicsurfaces of interest are the so called “lubricious” coatings, such asthose utilized in conjunction with catheters. These hydrophilic surfacesare often also covalently bonded, but may be just conformal coatings.Examples of chemical structures that occur in lubricious coatings arethose based on polyvinylpyrrolidone, hydroxyethyl methacrylate,poly(ethylene oxide) or poly(ethylene glycol) and the like.

Although shown and described is what is believed to be the mostpractical and preferred embodiments, it is apparent that departures fromspecific designs and methods described and shown will suggest themselvesto those skilled in the art and may be used without departing from thespirit and scope of the invention. The present invention is notrestricted to the particular constructions described and illustrated,but should be constructed to cohere with all modifications that may fallwithin the scope of the appended claims.

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 12. An implantable medical device comprising: a substantiallycylindrical intraluminal scaffold which is expandable from a firstdiameter for delivery into a vessel, to a second diameter for expandingthe vessel, the intraluminal scaffold having a luminal surface and anabluminal surface, the distance between the luminal surface and theabluminal surface defining the wall thickness of the intraluminalscaffold, the intraluminal scaffold also including a plurality ofopenings extending from the luminal to abluminal surface; a firstcoating comprising a material having a first electric charge affixed toat least a portion of the abluminal surface, the luminal surface and asurface of the plurality of openings; a second coating comprising amaterial having a second electric charge affixed to at least a portionof the first coating, the second electric charge being opposite of thefirst electric charge; and at least one therapeutic agent deposited inat least one of the plurality of openings, wherein the second coating isconfigured as an intermediate bonding layer between the first coatingand the at least one therapeutic agent.
 13. A method of coating anintraluminal scaffold having a plurality of openings therein, the methodcomprising applying a first coating comprising a material having a firstelectric charge to at least a portion of a surface of the intraluminalscaffold and a surface of the plurality of openings; applying a secondcoating comprising a material having a second electric charge to atleast a portion of the first coating, the second electric charge beingopposite of the first electric charge; and applying at least onetherapeutic agent into at least one of the plurality of openings. 14.The implantable medical device, according to claim 1, wherein the secondcoating comprises a polymeric polycation.